Centriole orientation and positioning are critical for the functions of centrioles, including the nucleation of motile cilia capable of generating coherent fluid flows in the proper direction, sensory cilia capable of sensing conditions at the appropriate location in a tissue, and positioning of mitotic spindles in the correct orientation during oriented cell division. However, the mechanisms that position and orient centrioles are almost completely unknown. The proposed experiments will explore the mechanisms that determine centriole position, using an integrated combination of genetic, proteomic, and imaging approaches. By identifying and analyzing genes with specific roles in centriole orientation and positioning, we hope to learn whether the different degrees of freedom of centriole orientation are independently regulated, and by what pathways;how centriole position relates to centriole duplication;and how individual elements of the centriole proteome contribute to centriole orientation. We expect that the genes thus uncovered would potentially constitute a new class of ciliary disease genes in which cilia form normally and retain normal function, but are located in the wrong position or beat in the wrong direction. PUBLIC HEALTH RELEVANCE: Centrioles are cylinder-shaped structures within the cell, and have been implicated in a host of human diseases including cancer and polycystic kidney disease. Our studies will investigate the pathways required to form these structures in the correct position, revealing a new set of candidate disease genes involved in regulating centriole orientation.